copper histidine saga review
TRANSCRIPT
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Coordination Chemistry Reviews 249 (2005) 895909
Review
The saga of copper(II)l-histidineP. Deschampsa, P.P. Kulkarnia, M. Gautam-Basakb,1, B. Sarkara,c,
a Depb
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8962. Detection of copper(II)l-histidine species in human blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8963. Equilibrium between copper(II)l-histidine species in aqueous solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
3.1. l-Histidine, a potential tridentate ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8973.2. Speciation of copper(II)l-histidine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
4. Coordination chemistry of copper(II)l-histidine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8994.1. Origin of the saga . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8994.2. Structures of the species in the copper(II)l-histidine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
4.2.1. MHL species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9004.2.2. MH2 L2 and ML species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9004.2.3. MHL2 species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9004.2.4. Physiological ML2 species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9014.2.5. MH1L2 species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
5. Copper(II)l-histidine complex as a copper transporter in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9035.1. Equilibrium in the exchangeable pool of copper(II) in human blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9035.2. Tissue and cellular uptake of copper facilitated by l-histidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9045.3. Kinetics of copper exchange with albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
6. Applications of copper(II)l-histidine complex as a therapeutic agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9056.1. Menkes disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9056.2. Infantile hypertrophic cardioencephalomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Abstract
Copperhuman blol-histidinel-histidineand in thephysiologic
CorrespoE-mail a
1 These co
0010-8545/$doi:10.1016is an essential trace element required by all living organisms. Since the discovery in 1966 of copper(II)l-histidine species inod, extensive research has been carried out to determine its role in copper transport. A small fraction of copper(II) bound tomaintains an exchangeable pool of copper(II) in equilibrium with albumin in human blood. The exchange of copper(II) betweenand albumin modulates the availability of copper to the cell. The role of l-histidine during its interaction with copper(II)albumincellular uptake of copper has generated considerable interest to determine the physico-chemical properties and the structure ofal copper(II)l-histidine complex. The structure of this complex remained inconclusive for the last four decades despite exhaustive
nding author. Tel.: +1 416 813 5921; fax: +1 416 813 5022.ddress: [email protected] (B. Sarkar).mments are those of the presenter/writer/editor only and do not necessarily represent the positions or policies of the FDA.
see front matter. Crown Copyright 2004 Published by Elsevier B.V. All rights reserved./j.ccr.2004.09.013artment of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ont., Canada M5G 1X8Ofce of New Drug Chemistry, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA
c Department of Biochemistry, University of Toronto, Ont., Canada M5S 1A8Received 29 June 2004; accepted 16 September 2004
Available online 26 November 2004
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896 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
characterization studies in aqueous solution. Recently, the physiological copper(II)bis(l-histidinato) complex has been crystallized andthe crystal structure has been solved. The structure shows a neutral five coordinate complex with a distorted square planar pyramidalgeometry. The unique structural features explain its thermodynamic stability and kinetic reactivity. This review summarizes the overallperspectives therapeutic applications of the physiological copper(II)l-histidine com H) has been widely used in the treatment of Menkes disease(a genetic n due to impaired copper metabolism) and more recent use hasbeen reporte thy (a condition caused by mutations in SCO2, a cytochromec oxidase asCrown Copy
Keywords: C t; Copperalbumin
1. Introdu
Copper(to its biochits differenery in 1966[1], extensits role inis shown tointo cellulacopper(II)of Menkes[2,3]. Recement of infalso been r
The phyand its thhowever that physiolfour decadaqueous soreported th[23]. Thisthe currentcopper(II)structure ois expectedresearch. Tstructural fin copperagent.
2. Detectihuman blo
Copper is an essential trace element required by all livingorganismsnent of manof copper abe extremetively low ccals throug
9]. This places a burden on systems that normally trans-copper between organs.opper exists only in bound forms in the body both inlloproteins and in low molecular weight complexes to
its inherent toxicity. There are excellent reviews writ-n recent years, which address various aspects of cop-etabolism, particularly the copper transport in human[3033]. Most of the copper in human blood is bound
ruloplasmin (9095%). However, there is 510% ofer in the oxidation state of 2+, which constitutes an ex-geable pool. Bearn and Kunkel [34] first demonstratedn plasma copper(II) was bound to albumin with a veryaffinit.4% o
ht cop. But
nd thoatureancesd thetitution
Fig. 1. Identification of copper(II)l-histidine complex in human blood
[24,25]. It plays a key role as an integral compo-y enzymes (Table 1) [26,27]. While trace amountsre required for normal metabolic processes, it canly toxic in excess [28]. Free copper, even in rela-oncentration, has the ability to generate free radi-h Fenton reaction and oxidize cellular components
serum by thin-layer chromatography. Autoradiographic picture of thin-layer chromatograms: (A) 64Cu(OH)2; (B) 64Cu-bis-l-histidine; (C) 64Cu-bis-l-threonine; (D) 64Cu + ultrafiltrate from dialyzed human serum; (E)64Cu + desalted serum ultrafiltrate. Analysis of the intense band in (E) hav-ing a similar Rf value as that of control 64Cu-l-histidine in (B) showed aCu:l-histidine molar ratio of 1:2 (reprinted with permission from Ref. [1];Copyright 1966 Academic Press).encompassing copper(II)l-histidine coordination chemistry andplex. The copper(II)l-histidine (1:2 complex at physiological p
eurodegenerative disorder that leads to early death in the childrend in the treatment of infantile hypertrophic cardioencephalomyopasembly gene).right 2004 Published by Elsevier B.V. All rights reserved.
opper; Copperhistidine; Menkes disease; X-ray structure; Copper transpor
ction
II)l-histidine system is of particular interest dueemical and pharmacological properties, as well ast possible coordination modes. Since the discov-of copper(II)l-histidine species in human blood
ive research has been carried out to determinecopper uptake into cells. Copper(II)l-histidine
be involved in copper transport before its entryr transport systems [2]. The transport properties ofl-histidine led to its application in the treatmentdisease, a fatal genetic neurodegenerative diseasently, the use of copper(II)l-histidine in the treat-antile hypertrophic cardioencephalomyopathy haseported [4,5].siological importance of copper(II)l-histidine
erapeutic applications are well known [15],e structure of copper(II)l-histidine complex
ogical pH remained inconclusive for the lastes despite exhaustive characterization studies inlution [622]. Recently, Deschamps et al. havee isolation and the X-ray structure of this complexdiscovery provides the opportunity to presentunderstanding of the coordination chemistry ofl-histidine system. The knowledge of the X-rayf physiological copper(II)l-histidine complexto provide further advances in its biochemical
his review will also discuss the insights intoeatures in relation to its physiological implicationsuptake into cells and its action as a therapeutic
on of copper(II)L-histidine species inod
[28,2port
Cmetaavoidten iper mbloodto cecoppchanthat ihigh0.20weigserum
[1] atrue nsubstsenteconsy. As early as 1954, Earl et al. [35] reported thatf unspecified amount of labeled low molecularper(II)-binding substances was ultrafiltrable init was not until the reports of Sarkar and Kruckse of Neumann and Sass-Kortsak [36] that theof these low molecular weight copper(II)-bindingbecame known. Neumann and Sass-Kortsak pre-evidence for an amino acid-bound fraction by re-
experiments [36]. Sarkar and Kruck detected and
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 897
Table 1Coppercontaining enzymes in humans
Copper enzymes Functional role Known or expected consequences of deficiency
Cytochrome cSuperoxide diTyrosinaseDopamine -Lysyl oxidaseCeruloplasmiEnzyme not k
Table 2Theoretical diblood plasma,7.4 (37 C, Naconstants [39,Complex spec
Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)Cu(II)(l-His)
a The perceblood plasmastudies did no
isolated comal humanThey showpredominawith mixedl-histidine
The forplexes has aComputatiopresence ohistidine coplexes invometric stab
3. Equilibspecies in
3.1. l-Hist
Amongmetal coordbinding ofpotential m(Ocarboxyl),nitrogen (Nresidues ofions are bo
Fig. 2.
g. 3 shs of lthe fondinged he[42].
le groof l-
alue ia mon
the pivelyoxidase Electron transport chainsmutase Free radical detoxification
Melanin productionhydroxylase Catecholamine production
Cross-linking of collagen and elastinn Ferroxidasenown Cross-linking of keratin
stribution of copper(II) in the ultrafiltrable fraction of normalas obtained by computer simulation in aqueous solution at pHClO4 0.15 mol dm3), using available stoichiometric stability40]ies log Percentage of ultrafiltrable coppera
(l-Gln) 16.70 19.22 17.50 15.5(l-Thr) 17.03 14.7(l-Ser) 16.97 7.5(l-Ala) 17.00 5.4(l-Lys)+ 17.05 4.4(Gly) 16.94 4.3(l-Asn) 16.81 4.2(l-Val) 16.93 3.9ntage of these species in the ultrafiltrable fraction of normalshould be considered with caution because these computationalt consider the copper binding to albumin in their calculations.
pper(II)l-amino acid complexes from the nor-blood serum using thin-layer chromatography [1].ed that copper(II)l-amino acid complexes exist
Fiformcise,respobe ustivelyidazoformpH vgivewhenspectntly as copper(II)bis-l-histidine complex alongcopper(II)l-amino acid complexes containing
ligand (Fig. 1).mation of mixed copper(II)l-amino acid com-lso been demonstrated in in vitro systems [37,38].nal studies on copper speciation supported thef comparable concentrations of copper(II)l-mplex and mixed copper(II)l-amino acid com-lving l-histidine ligand on the basis of stoichio-ility constants (Table 2) [39,40].
rium between copper(II)L-histidineaqueous solution
idine, a potential tridentate ligand
the amino acids, l-histidine is one of the strongestinating ligands and plays an important role in the
metal ions by proteins [27]. l-Histidine has threeetal-binding sites, namely the carboxylate oxygenthe imidazole imido nitrogen (Nim) and the aminoam) (Fig. 2). The imidazole nitrogen of l-histidine
ten provides the primary means by which the metalund to proteins.
which thequence inmetal-bindcriterion alnot be the schelate forthermodynnation [43]other factoment, whicexpressed iof the resulstabilizatiotions to theof the metnying metaOcarboxyl dfrom the retralization
As evidetate ligandthe pH of thare knowniological phas been eMuscle weakness, neurological effects, hypothermiaUncertainFailure of pigmentationNeurological effects, possible hypothermiaArterial abnormalities; loose skin and jointsAnemiaPili torti
l-Histidine, a potential tridentate ligand (HL form: 1).
ows the distribution of four different protonated-histidine as a function of pH [41]. To be con-llowing abbreviations H3L, H2L, HL, L cor-to different protonated forms of l-histidine, will
re. The pKa values are 1.8, 6.0, and 9.18, respec-The dissociation of the second proton of the im-up (pKa 14) is difficult to estimate. The majorhistidine at physiological pH is HL. When thes increased, the amine proton is deprotonated toonegative anionic ligand L. On the other hand,H value is lowered, the Nim and Ocarboxyl are re-protonated. It is most likely that the sequence inprotons are removed by titration is also the se-which the potential donor atoms are used in theing as the pH increases. However, the use of thisone is risky because the order of pKa values mayame as that of the enthalpy changes accompanyingmation, which provides a measure of the relativeamic stabilities of the metal-binding and proto-. Besides proton displacement reaction, severalrs are known to influence the structural arrange-
h include metalligand bond strengths (usuallyn terms of formation constants), stereochemistrytant complex, entropy of chelation and ligand fieldn energy. The most important negative contribu-enthalpies of chelation come from the formation
alNam bonds. The enthalpy changes accompa-lOcarboxyl are not favorable and the chelation ofepends on the increase in entropy, which resultslease of aquo-ligands and from the mutual neu-
of the metal and carboxyl group charges [43].nt,l-histidine can bind as a mono-, bi-, and triden-
and its mode of coordination implicitly depends one solution. All these different coordination modes
for cobalt(II)l-histidine system [44,45]. At phys-H, the tridentate chelation of l-histidine ligandstablished for bis-metal complexes of cobalt(II),
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898 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
histidine as a function of pH [41].
nickel(II), zthe stabilitplexes invo[50]. Coppwith the othighest valunique coo
3.2. Specia
The comper(II) andmetal ion t
For 1:1pH 6 [51].pH 5 no spspecies, thewhich maxremaining
Solutioncopper(II)most pHrium betweover a widspecies d
Table 3Logarithms o
StabilityConstantsa
Enthalpiesofformationa(kcal/mol)
a M+ L
HisH)]2+ (MHL), [Cu(His)]+ (ML), [Cu(HisH)2]2+2L2), +Cu(Histudyer(II)tions be ide
lity copH raationtheseted th
al pHrtant tce theion ofpper(IFig. 3. Distribution of various protonation forms of l-
inc(II), cadmium(II) [43,4649]. Table 3 presentsy constants and enthalpies of formation of com-lving l-histidine and different divalent metals ionser(II)l-histidine is the most stable in comparisonher metal(II)-l-histidine complexes. Further, itsue of negative enthalpies of formation suggestsrdination properties.
tion of copper(II)l-histidine system
position of the predominant complexes of cop-l-histidine in aqueous solution depends upon theo ligand ratio, temperature and pH.ratio, the [Cu(His)]+ (ML) species dominates atAbove pH 6 it is converted to ML(OH) and belowecies comprises more than 50% of all copper(II)greatest contributor being [Cu(HisH)]2+ (MHL)
imizes near pH 3.7 at less than 40%. Most of theligand is unbound at pH 3.7.
[Cu((MHand [tioncoppRela
Thstabiwideordinless,acceplogicimpofluenfunctof cos containing 1:2 or higher molar ratios ofto l-histidine possess the same species atvalues [8,20,52]. Fig. 4 shows the equilib-en these different copper(II)l-histidine speciese range of pH [8]. The copper(II)l-histidine
etected progressively as pH increases are:
f stability constants and negative enthalpies of formation [50]Co(II) Ni(II) Cu(II) Zn(II) Cd(II)
logK1 6.9 8.7 10.1 6.6 5.4logK2 5.5 6.9 8.0 5.5 4.3
H1 9.6 16.2 21.0 11.6 H2 12.3 16.6 21.3 11.7
ML (K1,H1),ML+ L ML2 (K2,H2).
Fig. 4. Specieof pH in 1:8 c(3) ML; (4) ML: l-histidine[8]; Copyrighspecies are de[Cu(His)(HisH)] (MHL2), [Cu(His)2] (ML2)s)2(OH)] (MH1L2). Results of this detailed titra-indicate that among all these species, the majorl-histidine species are MHL, MHL2 and ML2.etween these species are summarized in Fig. 5.
ntification of copper(II)l-histidine species, theirnstants and their quantitative distribution over ange provide a suitable basis for studying the co-chemistry of this system in solution. Neverthe-results must be used with caution. It is generallyat only ML2 species is present around physio-in aqueous solution (>99% at pH 7.4). But, it iso note that the experimental conditions clearly in-copper(II)l-histidine species distribution as apH values. For example, a change of molar ratioI):l-histidine from 1:8 to 1:10 at fixed tempera-s distribution in the copper(II)l-histidine system as a functionopper(II):l-histidine molar ratio. (1) Unbound M; (2) MHL;H2L2; (5) MHL2; (6) ML2; (7) MH1L2 (M: copper(II),
, charges are omitted) (reprinted with permission from Ref.t 1973). (Please note the detailed structures of these differentscribed in Section 4.2.)
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 899
Fig. 5. Relatipresent in aquwere determin
Fig. 6. Polarotion in 1:20 mof one copperT= 298 K, ph1 cm 0.125
ture and pHhistidine spthe formatiphysiologicidazole nitrof excess h6.87.3, excomplexes,copper(II)larographicpresence ofological pH(Fig. 6) [41potential vaby polarog
4. Coordinsystem
4.1. Origin
A majorand structu
. Commnating se ring.
d, theof coninatiopper(Ilexedof cooatten
rted ocr theore c
givingberedentialdepen, beingially wermo
identaer(II)on between the predominant copper(II)l-histidine specieseous solution. Logarithms of stoichiometric stability constantsed at 25 C and 0.1 ionic strength [8].
Fig. 7coordichelat
Indeebeencoordof cocomprietynar, fldisto
Fothe mtionmem
a potetryacidsespecthe ththe bcoppgram in impulsional mode of a copper(II)l-histidine solu-olar ratio at pH 7.4. Each peak corresponds to the detection
(II)l-histidine species present in solution ([Cu2+] = 103 M,osphate buffer, 1 mL gelatine, 1 cm 100 mV/SCE andA) [41].
values induces a slight shift in the copper(II)l-ecies distribution [8]. An EPR study suggestedon of [Cu(II)(l-His)4] in frozen solution aroundal pH [14]. It is proposed that four equivalent im-ogen atoms are bound to copper in the presenceistidine. In this case, the conditions used: pH ofcess of ligand, rapid freezing and immobilizedall have contributed to the formation of this 1:4l-histidine form. In the same way, a recent po-analysis in impulsional mode shows a significantdifferent copper(II)l-histidine species at physi-in a large excess of l-histidine ligand in solution]. Each copper species has a specific half wavelue at fixed pH, allowing its detection in solution
raphy in impulsional mode.
ation chemistry of copper(II)L-histidine
of the saga
effort was made to study the stability, speciationre of copper(II)l-amino acid complexes [53,54].
cal manifesordinationnearby donaround thedistant axiateracts withwith coppe
The sterfactor in thcomplexesboth cis- anacids are othe same sand on oppmajor compbetween thfive-membwill be gov
The comstructuralcomplex. Ca unique cagation of itsin bidentatenot occupyquestion araround coption modessearchers.on bidentate chelation mode of amino acids with non-ide chains forming thermodynamically stable five-membered
copper(II) interactions with amino acids havesiderable interest because of their various possiblen geometries. From the reported crystal structuresI)l-amino acids complexes [5560], copper(II)with l-amino acids has been shown to adopt a va-rdination geometries (from distorted square pla-
ed tetrahedral and distorted square-pyramidal totahedral).amino acids with non-coordinating side chains,ommon mode of coordination is bidentate chela-rise to the more thermodynamically stable five-
chelate ring (Fig. 7) [54]. For the amino acids withcoordinating side chain, the coordination geom-
ds on the nature of the metal ions. Many aminopotentially tridentate, binds as bidentate ligands,ith a metal ion such as copper(II). In addition to
dynamic stability of five-membered chelate ring,te chelation is facilitated by the softness of thecoordination sphere induced by the stereochemi-tation of the JahnTeller effect [6163]. The co-
compounds of copper(II) generally consist of fouror atoms arranged approximately in a square planemetal ion, with the possibility of one or two morel donors [53,64]. At neutral pH, l-glutamine in-Co(II) and Ni(II) as a tridentate ligand, but not
r(II) [54,60].eoselectivity of amino acids is another importante coordination mode of copper(II)l-amino acid[54]. In the equatorial plane of bis-complexes,d trans-isomers are possible. If the two l-amino
f the same chirality, both side chains will be onide of the coordination plane in the trans-isomerosite sides in the cis-isomer. The formation of thelex will depend on the relative energy differences
e cis- and trans-isomers on the one hand and theered chelate ring on the other. The steric controlerned by whichever is the larger.bination of all these factors induces a specific
arrangement for each copper(II)l-amino acidopper(II)l-histidine system can be considered asse due to the difficulties encountered in the investi-coordination modes. l-Histidine may be chelatedmode. The three donor atoms of l-histidine can-the same plane and if l-histidine is tridentate, theises as to which ones occupies the planar positionper(II). For the last four decades, the coordina-of copper(II)l-histidine has baffled many re-
Almost all the possible coordination modes have
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900 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
Fig. 8
been proposaga of co
4.2. Structcopper(II)
In aquesumes varivalue. Bothidentified.on the studby single-c
4.2.1. MHAt pH 2
the ionizabtrogen Nimto be evidenture 2 is shis the mostalso been snearly iden3 forMHL3, the imiding to copppresent indination m
4.2.2. MHMH2L2
almost theavailable wspecies whsolved byisomer MHOcarboxyl atThe Nim atoThe mode oplanar withThere arethis plane,binding mo
9. X-ray structure of the complex ion MH2L26H9O2N3)(H2O)2]2+ (4) and predictive structure of ML (5).
, shows that the sequence in which the protons of l-ine are removed is not the sequence in which potentialr atoms are used in the metal-binding. It was suggestedakineerionithe amis difnt ofL2. N
d the pI) coo[911
vemenstudi
ly boug. 9.
. MHe stru
e tridecarbolutionear pHtidine-chelon bee stru
vis sp. Two different proposed structures of MHL [9,11].
sed for ML2 complex. This is the origin of thepperhistidine.
ures of the species in thel-histidine system
ous solution, copper(II)l-histidine system as-ous coordination modes depending on the pHmono- and bis-l-histidine complexes have been
Here, we describe the predictive structures, basedies carried out in solution and those determinedrystal X-ray diffraction method.
L species, the predominant species isMHL. The location ofle proton in MHL is uncertain. The imidazole ni-and the carboxyl oxygen Ocarboxyl bindings seemt from the IR results [9]. The corresponding struc-own in Fig. 8. This proposed coordination modeaccepted [51,65], but another chelation mode hasuggested [6,11]. Casella and Gullotti [11], usingtical conditions, proposed the coordination modebecause their CD studies suggested that below pH
azole group of l-histidine is not involved in bind-er(II) (Fig. 8). The coexistence of several speciessolution may explain the uncertainty about coor-ode of l-histidine in MHL.
2L2 andML speciesandML species show maximum concentration at
same pH. For a long time, the only X-ray structure
Fig.[Cu(C
shellhistiddonoby Mzwittfrom
Itamou
MH2lisheper(Imentinvolsome
weakin Fi
4.2.3Th
of onaxialin sotra nl-hisa non
relatidictivUVas that of MH2L2. The X-ray structure of thisich crystallized from a solution at pH 3.7 has beenEvertsson [66]. The structure of cationic trans-2L2 (4) species showed that two Nam and two
oms are coordinated to the copper(II) ion (Fig. 9).ms, being protonated, are not bound to copper(II).f coordination around copper(II) center is squarethe four donor atoms situated at 1.932.00 A.
two water molecules, one above and one belowat distances of 2.46 and 2.78 A, respectively. Thisde, involving Nam atoms in the first coordinationn et al. [67] that copper(II) reacts with the neutralc l-histidine followed by a rapid proton transfer
ino group to the imidazole ring.ficult to elucidate the structure of ML since thethis species is always exceeded by either MHL orevertheless, ESR, CD and electronic data estab-resence of two nitrogen donor atoms in the cop-
rdination environment in a square planar arrange-]. The IR data also showed carboxylate groupt in the first coordination shell [9]. Nevertheless,es suggested that the carboxylate group is onlynd [6]. The predictive structure 5 of ML is shown
L2 speciescture of MHL2 is considered to be a combinationntate l-histidine ligand with a weakly coordinatedxylate group and one bidentate l-histidine ligand[911,19]. The visible absorption and CD spec-5 are similar to that of the mixed complex with
and l-1-methylhistidine, a bidentate ligand withatable imidazole group [50]. A simple acidbasetween MH2L2 and MHL2 is observed. The pre-cture 6 ofMHL2, deduced from IR, ESR, CD andectroscopies, is presented in Fig. 10 [911,19].Fig. 10. Proposed structure of MHL2 (6).
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 901
4.2.4. PhysiologicalML2 species4.2.4.1. Structural studies in solution. Extensive researchhas been carried out to determine the structure of physiologi-cal copper(II)l-histidine complex. Despite efforts by manylaboratories to crystallize the ML2 complex, such attemptsoften led to the formation of dark solution due to the sensitiv-ity of this complex to light and oxygen. These unsuccessfulresults to crystallize ML2 complex led many researchers tofocus on studies in aqueous solution by various spectroscopictechniques such as IR, 13C- and 1H NMR, ESR, ENDOR, Ra-man, UVvis, CD and EXAFS [6,7,922]. Even with all thesestudies, the greatest uncertainty remained for the structure ofML2 in aqueous solution. This complex has been variouslydescribed as coordination mode involving (a) the amino andimidazole groups in the square plane, (b) the amino and car-boxylate groups in the square plane. Yet other studies havesuggested mixed binding modes for l-histidine ligands. Thissaga of coordination chemistry of copper(II)l-histidine atphysiological pH was further compounded by many studiesreporting that an equilibrium between two different coordi-nation configurations may also be possible.
Fig. 11. X-ra is)(l-Tand [Cu(II)(l
The involvement of Ocarboxyl in axial position was beyondspeculation for some studies. The formation constant [19],enthalpy of formation [68] and degradability by H2O2 [65]of copper(II)l-histidine complex at pH 7.4 are very similarto those of copper(II)histamine complex formed under thesame conditions. Histamine has no carboxyl group, so it wassuggested that the metal must be bonded only to the Namand Nim atoms. Nevertheless, some studies suggested thatthe Ocarboxyl of first l-histidine ligand may be coordinated inan apical position, though it is strained [2].
4.2.4.2. Model compounds of the structural arrangement ofML2 complex. Several X-ray crystal structures of copper(II)complexes provided insights into a possible arrangementbetween copper(II) and l-histidine. In earlier studies fromour laboratory, we have crystallized the complex [Cu(II)(l-His)(d-His)(H2O)2]4H2O (7) at pH 8 (Fig. 11) [69]. The cop-per atom is octahedrally coordinated by Nam and Nim atomsof l-histidine and d-histidine in a square planar arrangementand by oxygen atoms of water molecule at the axial posi-tions. The Cu(II)N distances are 2.03 A (Nam) and 2.00 Ay crystal structures of [Cu(II)(l-His)(d-His)(H2O)2]4H2O (7), [Cu(II)(l-H-His)(l-Asn)] (10) [69,7173].hr)(H2O)]H2O (8), [Cu(II)(l-His)(l-Asn)(H2O)]3H2O (9),
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902 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
(Nim) and the CuOH2 separation is 2.57 A. The carboxy-late groups of histidine molecules secondarily coordinate tothe copper(II) through hydrogen bonding to the axial watermolecules. This structure shows the involvement of both im-idazole groups in trans-geometry. It is interesting to note thatthe crystal structure of [Cu(II)(histamine)2](ClO4)2 has alsobeen determined and the structural features are very simi-lar to 7 [70]. Four nitrogen atoms occupy the coordinationplane with two axial perchlorates. The nitrogen donor atomsfrom two planar imidazole rings occupy trans-coordinationpositions at 1.98 A from the copper(II) center.
In mixed copper(II)l-amino acid complexes, suchas [Cu(II)(l-His)(l-Thr)(H2O)]H2O (8), [Cu(II)(l-His)(l-Asn)(H2O)]3H2O (9), and [Cu(II)(l-His)(l-Asn)] (10) com-plexes, l-histidine acts as a tridentate ligand (Fig. 11)[7173]. The X-ray analyses of these complexes revealedthat they have the same structural features. Interestingly, thestructures 9 and 10 show different conformations of the polarside chain of l-asparagine. For the tetrahydrated complex, theside chain is stretched while the anhydrous complex presentsa bent side chain. Both amide groups of l-asparagine ligandare H-bonded to adjacent complex molecules and/or watermolecules. It has been suggested that the amide nitrogen ofthis polar side group may form a H-bond with the axially co-ordinated Ocarboxyl of l-histidine ligand by rotation aroundthe C C bond and a slight deformation of the chelate ringfor the anhydrous complex [74].
Duringcopper(II)crystallizedhistidine li
Fig. 12. X-dimethylbutyimidazol-4-yl
The copper(II) ion is coordinated by a tetradentate lig-and with the amino and imidazole imido nitrogen atomson one side versus imino nitrogen and carboxylate oxygenatoms on the other side in a distorted square-planar geom-etry. The novel ligand is obtained by the reaction betweenthe l-histidine molecules coordinated to copper(II) and 4-hydroxy-4-methylpentan-2-one formed by aldol condensa-tion of acetone. Two oxygen atoms complete the distortedoctahedral coordination sphere. The first oxygen atom is orig-inated from carboxylate group of the first l-histidine ligandat 2.50 A and the other oxygen atom is provided by symme-try. This compound presents similar structural features thatthose of mixed copper(II)amino acid complexes [75].
4.2.4.3. X-ray crystal structure of ML2. Recently, De-schamps et al. reported the isolation and the X-ray struc-ture determination of the physiological ML2 species [23].Fig. 13 shows the X-ray crystal structure of ML2 (12), aneutral five coordinate distorted square-pyramidal complex.One of the l-histidine ligands acts as a monoanionic bidentateform through Nam and Ocarboxyl atoms. While the other bindsin monoanthrough itslies in an a
The X-rtures suspelogical pH
andin pr
to exphe las
was
ach tefeaturI)Nimuch axylate
3. X-raour recent efforts to elucidate the structure ofl-histidine species at physiological pH, first we
a novel copper(II) complex with modified l-gand (Fig. 12) [75].
ray crystal structure of Cu(II)A with A= 2-[(1,3-lidene)-3-N(1-(1H-imidazol-4-yl)ethanoic acid)]-3-(1H-) propanoic acid [75].
as pHtimescientfor tof 12that eturalCu(Iies, scarbo
Fig. 1ionic tridentate ligand towards copper(II) centerNam, Nim, and Ocarboxyl atoms. The Ocarboxyl atomxial position.ay structure obtained is different from all the struc-cted for copper(II)l-histidine species at physio-in solution to date. The important variables suchligand-to-metal ratios were not considered some-evious studies, but this aspect alone is not suffi-lain the inconclusive structural results in solution
t four decades. It is likely that the exact naturedifficult to determine in solution due to the factchnique allowed the identification of some struc-es but not all. The strong fingerprint of the bindingcould be misleading in many spectroscopic stud-
s CD and UVvis analyses. The involvement ofgroups was indicated by IR studies, but the num-
y crystal structure of physiological ML2 complex (12) [23].
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 903
ber of Ocarboxyl group(s) involved in the first coordinationshell of copper(II) was not conclusive.
The structural arrangement in the complex 12 is the resultof a combil-histidinesquare planto copper(Iunfavorabltridentate lfurther failin the coorl-histidinein the coorelectrostatipendant iml-histidineplex 12. ThHis)(H2O)this case thgeometry. Ttamine as mis different
The inteaqueous soat pH 7.4.was addedcrystallizatsmall clustand presenthe crystalcrystal struis greatlyformed betatoms fromor more w
copper comof hydrogeacids oxyprocess, thtions involin aqueouspreceded b
The bidorder. Theconformatiligand. Thein the crystreorientatiodue to H-boto resolve tstretched obonding in
4.2.5. MHThe spe
No structur
because of the instability of the copper(II)l-histidine systemin the pH range above 9. At high pH, the loss of proton couldresult either from the addition of OH or the pyrrole hydrogen
ation.
opper(II)l-histidine complex as a copperporter in humans
Equilibrium in the exchangeable pool of copper(II)man blood
human blood, albumin binds copper with very highty and thus acts as a buffer against copper toxicity7]. Equilibrium dialysis, visible spectroscopy and pro-isplacement studies demonstrated the presence of a sin-igh affinity copper(II)-binding site on albumin [78,79].N-terme amibindiner(II)-amino,
ue inl sidebeen r
in [8I) to hsine ragne
tion oAlaHsmallan ex
in inexcluixed
ine liand m-histidant vares beixed
. Prop3).nation of steric effect induced by the tridentateligand and the preference of copper(II) ion for aar geometry. Only one imidazole group is boundI) center and the other imidazole is trapped in ane position closed to the axial Ocarboxyl group of the-histidine ligand. This pendant imidazole group
s to rotate in proximity to the remaining axial sitedination sphere due to the S-stereochemistry ofligand. The stereoselectivity is a crucial factordination mode of l-histidine ligands. It inducesc interactions, such as H-bonding involving theidazole and the carboxylate group of tridentateand could explain the excellent stability of com-e presence of racemic ligands in [Cu(II)(l-His)(d-2]4H2O decreases the steric effects, explaining ine involvement of both imidazole groups in trans-his factor was not considered with the use of his-odel and it explains why the coordination mode
with l-histidine in solution.nse blue crystals of 12 were obtained from an
lution of copper(II)l-histidine in 1:2 molar ratioA volume of N,N-dimethylformamide (DMF)to make 50/50 v/v water/DMF mixture. The
ion induced by slow diffusion of ethanol yieldeders. Isolation of 12 was facilitated by its solubilityce of pendant basic imidazole group that assistgrowth through non-covalent interactions. The
cture of aquocopper(II)l-amino acid complexesdominated by intermolecular hydrogen bondsween water hydrogen atoms and carbonyl oxygen
the surrounding molecules [76]. When twoater molecules are present in crystal lattice, theplexes are additionally linked through a network
n bridges between water molecules and the aminogen and nitrogen atoms. In our crystallizatione addition of DMF reduces H-bonding interac-ving the pendant imidazole group and anionssolution facilitating the crystallization process
y the salt precipitation.entate l-histidine ligand shows a positional dis-observed disorder is due to the presence of twoons of the side chain of the pendant l-histidinewater molecule (O2WB) was only half occupied
al structure of 12 and it appears that it caused then of the unbound imidazole when it was presentnding to N(5). The use of other solvents could helphe observed disorder in 12 facilitating either ther the bent configuration by reducing or growing H-teractions involving the pendant imidazole group.
1L2 speciescies MH1L2 is formed at a pH greater than 8.al assignment of this species is proposed. This is
ioniz
5. Ctrans
5.1.in hu
Inaffini[24,7ton dgle hTheof thcificcoppthe Nresidboxyalsoalbumper(Ithe lyparamturbaAsp
Atainsalbummostand mhistidplexing lconstfeatuthe m
Fig. 14min (1inal region of albumin, with the involvementno acid sequence AspAlaHis, provide a spe-g site for copper(II) ion (Fig. 14) [8084]. Thetransport site on albumin was suggested to involvetwo Npeptide, and the Nimidazole of the histidine
position 3 in a square planar geometry. The car-chain of the amino-terminal aspartyl residue haseported to be involved in copper(II) chelation for0]. A more recent study on the binding of cop-uman albumin suggested also the involvement ofesidue [85]. This 1H NMR analysis shows that thetic effects due to copper(II) caused specific per-f the resonances for the three N-terminal residuesis as well as those for Lys.fraction of copper bound to l-amino acids main-changeable pool of copper in equilibrium withhuman blood [1]. This fraction is constituted al-sively of binary copper(II)l-histidine complexcopper(II)l-amino acid complexes involving l-gand [1,37,38,86]. Copper(II)l-histidine com-ixed copper(II)l-amino acid complexes involv-ine ligand have similar stoichiometric stabilitylues (log 1718). The similarity of structuraltween copper(II)l-histidine complex (12) andcopper(II)l-amino acid complexes involving l-
osed structure of the Cu(II)-binding site of human serum albu-
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904 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
Table 4Structural features of the first coordination shell of copper for some copper(II)amino acid complexes involving l-histidine ligandCopper complexes Coordination binding of l-histidine ligands Atoms involved Distances CuX (A) Ref.Cu(II)(l-His) Nam
NimOcarbNamOcarb
Cu(II)(l-His) NamNimOcarbNamOcarb
Cu(II)(l-His) NamNimOcarbN#carbO#carb
* and # are as ely.
histidine livalues of this suggesteconcentrati
The tridands is anof copper(Iligand. Thibinary copchiometricl-amino acligible conman bloodcopper(II)only to thethe centralgroup in anamicallynon-covaleon the stabseveral mixattributed t
5.2. Tissuel-histidine
Experimhistidine e[8890]. Si[91]. In vitfacilitate coknowledgehistidine coing of the b[23]. The ctridentate lbinding ofcomplex 12
tructuossiblin reco
recepole ofer(II)formavemenld be pophobaracte
e bidetive des.
Kineti
opperwhile5]. Thin m
e has bn com2 Tridentate
Bidentate
(l-Thr) Tridentate
Bidentate
(l-Asn) Tridentate
Bidentate
sociating to atoms originating from l-threonine and l-asparagine, respectiv
gand is consistent with similar stability constantese complexes (Table 4). This could explain why itd that these different complexes are in comparableons in human blood [39,40].entate chelation of one of the l-histidine lig-important factor in the thermodynamic stabilityI)l-amino acid complexes involving l-histidines provides an additional stability over the otherper(II)l-amino acid complexes. The lower stoi-stability constant values of other copper(II)bis-id complexes (log 1213) can explain the neg-centrations of these complexes detected in hu-[5560]. Nevertheless, the enhanced stability ofbis-l-histidine (log 18) cannot be attributedfive coordinate geometry. The asymmetry aroundcopper(II) and the involvement of carboxylate
xial position may reflect themselves thermody-in terms of entropy change in the system. Thent bonds may also have a considerable influenceility of these complexes. Enhanced stability ofed copper(II)l-amino acid complexes has been
o electrostatic ligandligand interactions [87].
The sthe ptionbranethe rcoppTheinvolshouhydrsic chof theffecbrane
5.3.
C[93][94,9albumdencnatioand cellular uptake of copper facilitated by
ents with hepatic tissues demonstrated that l-nhances the uptake of copper in hepatic cellsmilar results have been obtained in placental cellsro studies have demonstrated that l-histidine canpper uptake in mammalian brain [92]. The recentof the structure of the physiological copper(II)l-mplex is a major breakthrough in our understand-iochemical aspects of its role in copper transportoncurrence of the high stability associated withigation and the kinetic lability of the bidentatel-histidine ligand highlight the contribution ofin the copper transport across cell membranes.
under physspectroscopnative seqand l-histiplexes CuHnote the anl-histidineand Sarkarreaction ofmethyl amThe reactiovolving cohistidine castructure ocopper-tran2.003 [23]1.984
oxyl 2.2772.034
oxyl 1.9572.01 [71]1.95
oxyl 2.582.00
oxyl 1.972.03 [73]1.94
oxyl 2.39oxyl 1.95oxyl 1.99
ral elucidation of 12 gives insights to understande role of hydrophobicity, surface charge distribu-gnition as well as its binding on the cell mem-tor. Further research in this area should explorependant protonated imidazole in the transport ofl-histidine complex across cellular membrane.tion of copper(II)l-histidine complex with thet of weak intramolecular H-bonding interactionsarticularly favored in the transport of copper in theic environment of biological membranes. The ba-r of imidazole group and H-bonding interactionsntate l-histidine ligand can also be used for thelivery of radio imaging agents across cell mem-
cs of copper exchange with albumin
transport in the tissues is facilitated by l-histidinealbumin inhibits the copper uptake into the cellse exchange of copper(II) between l-histidine andodulates the availability of copper to the cell. Evi-een presented for the existence of a ternary coordi-plex between albumin, copper(II) and l-histidine
iological conditions [79]. The equilibrium andic studies of the ternary system: copper(II), the
uence tripeptide AspAlaHis-N-methyl amidedine show the formation of mixed ligand com-1AL (15) and CuAL (14) (where A and L de-
ionic forms of AspAlaHis-N-methyl amide and, respectively) at physiological pH [82,83]. Tabata
[82,83] studied the kinetics for copper-transferthe native sequence tripeptide, AspAlaHis-N-
ide and l-histidine over a pH range of 6.510.0.n mechanism for the copper-transfer reaction in-pper(II), AspAlaHis-N-methyl amide and l-n be described in the light of recent X-ray crystalf physiological ML2 species (Fig. 15). For thesfer from copper(II)l-histidine complex to na-
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 905
Fig. 15. Propto both l-hist
tive sequenformationCuH1ALtide nitrogcopper(II)ing step inpeptide nitrprotonationfeatures ofanism mayamino acid
6. Applicaa therapeu
6.1. Menke
Menkescauses rapidisease maosed reaction mechanism for the copper-transfer reaction involving copper(II), Aspidine and another l-amino acid (adapted from Ref. [82]).
ce peptide, the rate-determining step is a bondbetween copper(II) and peptide nitrogen to form
(15) from CuAL (14) by deprotonation of pep-en atom. For the copper-transfer reaction frompeptide complex to l-histidine, the rate determin-volves a bond breaking between copper(II) andogen to formCuAL (14) fromCuH1AL (15) byto a peptide nitrogen. According to the structuralcopper(II)l-histidine complex, a similar mech-be considered in the case of mixed copper(II)l-complexes involving l-histidine ligand.
tions of copper(II)l-histidine complex astic agent
s disease
disease is a fatal X-linked genetic disorder whichdly progressive cerebral degeneration [96]. Thenifests itself with severe mental retardation, con-
vulsions, gpili torti, aChildren uical basis oin intracellease fibrobof copper,[111,112].duced duecopper. Thels of deve[24]. Deficfor the clinclinical hetmild forms(9095%)gene (ATPis expresseliver [116].responsiblebranes. HoAlaHis-N-methyl amide and l-histidine. l-AA corresponds
rowth retardation, hypothermia, skeletal changes,nd connective tissues abnormalities [3,97108].sually die before the age of three. The biochem-f this disease is related to a widespread defect
ular copper transport [98,109,110]. Menkes dis-lasts in culture show a significant accumulationbut the efflux of copper from the cell is reducedSerum copper and ceruloplasmin levels are re-to the impairment of the intestinal absorption ofe lack of available copper leads to decreased lev-lopmentally important copper enzymes (Table 1)iencies of copper enzymes are thought to accountical manifestations of this disease [3]. There iserogeneity in Menkes disease. Although there aresuch as occipital horn syndrome, most patients
present the severe form [113]. The responsible7A or MNK) was isolated in 1993 [114116]. Itd in all tissues although only in trace amounts inIt encodes a copper-transporting P-type ATPasefor the transportation of copper across cell mem-
wever, this role alone would not fully explain the
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906 P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909
Fig. 16. Effec loplasmpatient was un ring thechanged to da smin lesuspended for supran
clinical maprotein is aintracellula
Treatmerestoring ncopper. SinMenkes paThere is anAs describaffinity inthe cells [2induces theand therefocells [118].copper saltlevel (Fig.therapy wiper sulfateing eitherbeen succetion causedment of Mreaction bemust be inof copper.the exchanin the prespropertiesits applicatease [113,1follow-up o[122]. Theschemical im
ical oave borldsficantof Menue tored bytions oe, havnal and
comprly treduringt of subcutaneous administration of copper(II)l-histidine on serum cerusuccessfully treated with daily intravenous injections of copper chloride du
ily subcutaneous injections of copper histidine. A normalization of cerulopla1 month at age 11 months because the plasma ceruloplasmin level became
nifestations of Menkes disease. It is likely that thelso involved in the transport of copper into somer organelles [30,117].nts for Menkes patients have concentrated onormal copper levels in the body by administeringce intestinal copper absorption is extremely low intients, copper must be administrated parenterally.other obstacle in delivering copper into the cells.ed earlier, albumin binds copper with a very highhuman blood and inhibits the copper uptake into4,77,94,95]. The administration of copper saltsformation of copperalbumin complex in blood
re copper in this form is not bio-available to the
rologels hthe wsignimentcontirestoinjecin lifratioriousof eaableThe patients treated with intravenous injections ofs did not show a normalization of ceruloplasmin16) [118,119]. This explains why the parenteralth various copper forms (copper chloride, cop-, copper EDTA and copper albumin) commenc-before or after neurological impairment, has notssful in resisting the progressive neurodegenera-by the disease [118]. To achieve an efficient treat-
enkes disease, the equilibrium of copper-transfertween albumin and the administrated copper formfavor of the formation of the bio-available formAs reported earlier, kinetic studies demonstratedge of copper(II) between albumin and l-histidineence of an excess of l-histidine. The transportof the copper(II)l-histidine complex led us toion as a therapeutic agent to treat Menkes dis-20123]. We have previously reported a long-termf four patients treated with copper(II)l-histidinee patients have shown significant clinical and bio-provement. They all show relatively good neu-
nervous syatively unsour knowleare currenthistidine inbetter form
6.2. Infant
Humanciated withMutationsresult in aopathy (HC[4,126]. Alure due to Hsertion of coxidase hobroblasts, mshown thatin level in a Menkes patient (adapted from Ref. [119]). Thethree 3 months. From age 3 months (Feb 16th) treatment was
vel was observed. Copperhistidine treatment was temporarilyormal.
utcome and the serum copper, ceruloplasmin lev-een normalized (Fig. 16) [119]. They representlongest surviving Menkes patients. Despite theseimprovements in the copper(II)l-histidine treat-nkes disease patients, connective tissue disorderspersist, indicating that lysyl oxidase levels are notcopper(II)l-histidine treatment. Subcutaneous
f copper(II)l-histidine when initiated very earlye been tolerated best and seem to be the mosteffective treatment in preventing some of the se-
lications of Menkes disease [122]. The efficacyatment may be the result of making copper avail-
a critical period of development of the central
stem. The copper(II)l-histidine complex is a rel-table inorganic complex in aqueous solution. Todge, many formulations of copper(II)l-histidinely used [2,41,124]. The isolation of copper(II)l-the solid state allows us to consider a novel and
ulation for the treatment of Menkes disease.
ile hypertrophic cardioencephalomyopathy
mitochondrial disorders are clinical entities asso-abnormalities of oxidative phosphorylation [125].in SCO2, a cytochrome c oxidase assembly gene,fatal infantile hypertrophic cardioencephalomy-M) with severe cytochrome c oxidase deficiency
l patients reported so far have died from heart fail-CM. Human SCO2 seems to be involved in the in-
opper atoms into the mitochondrial cytochrome cloenzyme. Several studies in yeast, bacteria and fi-
yoblasts from patients with SCO2mutations havecopper supplementation can restore cytochrome c
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P. Deschamps et al. / Coordination Chemistry Reviews 249 (2005) 895909 907
oxidase activity to almost normal levels [125,127,128]. Theseresults suggested a possible therapy for the early treatmentof this fatal infantile disease by increasing the intracellularcontent ofcessful trea[5] recentlysupplemenin severe hydescribed tand who suto all the pCopper(II)probable etion in thisto generaliz
7. Conclu
Copper(Subsequenthe cellulabetween l-of copper tcopper(II)stabilities aies led to thMenkes diswhich theto crucial eand the X-rhistidine cothe high stkinetic reaclight the cothe presencdant imidaplex may breceptor ulthe cell. Thvide furthecopper(II)plications a
Acknowled
Researcthe MedicaInstitutes oand co-wor
Reference
[1] B. Sar(Eds.),p. 183.
[2] B. Sarkar, Chem. Rev. 99 (1999) 2535.[3] D.M. Danks, in: C.R. Scriver, A.I. Beaudet, W.S. Sly, D. Valle
(Eds.), Metabolic Basis of Inherited Disease, McGraw-Hill, NewYork, 1L.C. PNishinoGlerumS. ShaE.A. SP. FreiInherit.E.W. W(1970)H. SigT.P.A.T.P.A.B.A. Gton TraL. CasG. ValBiocheB. HenR. BasGierulaM. PasJ.S. HyM. RoM. CoM. CoT. Szab(2000)R. GroShoonh122 (2I. NicoJ.C. C(2001)P. ManP. Des3338.M. DiDB.G. M286.I. BerHandboBioinoE.I. So(1996)L.M. GH.H. SC.D. VB. SarkE.D. HN. FateA.G. B44.C.J. Ea205.P.Z. NeB. SarkB. Sark46 (19V. Bru287.P.M. MteractioDekkercopper in critical tissues. On the basis of the suc-tment of Menkes disease, Jaksch and co-workers
suggested subcutaneous copper(II)l-histidinetation for a patient with SCO2 mutations resultingpertrophic cardioencephalomyopathy. This studyhe first patient who showed a reversal of HCMrvived significantly longer (42 months) comparedreviously reported patients (longest 13 months).l-histidine supplementation might be the mostxplanation for the improvement of cardiac func-patient [5]. However, further studies are requirede the use of this treatment.
sion
II)l-histidine was discovered in human blood.tly, it was demonstrated that l-histidine enhancesr uptake of copper and the exchange of copperhistidine and albumin modulates the availabilityo the cell. A major effort was made to study thel-histidine system to establish the distribution,nd structures of different species. All these stud-e use of copper(II)l-histidine in the treatment ofease and HCM. Nevertheless, the mechanism bycopper(II)l-histidine complex provides coppernzymes remained unclear. Recently the isolationay crystal structure of physiological copper(II)l-mplex have been reported. The concurrence of
ability associated with tridentate ligation and thetivity of the bidentate ligation of l-histidine high-ntribution of this complex in copper transport ine of albumin in human blood. Further, the pen-
zole observed in the copper(II)l-histidine com-e the key to its interaction on the cell membranetimately modulating the availability of copper toe knowledge gained from these studies will pro-r advances in our understanding of the role ofl-histidine in normal physiology and in its ap-s a therapeutic agent in diseases.
gements
h in the laboratory of B. Sarkar was supported byl Research Council of Canada and the Canadianf Health Research. Authors thank many colleagueskers whose names appear in the references.
s
kar, T.P.A. Kruck, in: J. Peisach, P. Aisen, W. BlumbergBiochemistry of Copper, Academic Press, New York, 1966,
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The saga of copper(II)-l-histidineIntroductionDetection of copper(II)-l-histidine species in human bloodEquilibrium between copper(II)-l-histidine species in aqueous solutionl-Histidine, a potential tridentate ligandSpeciation of copper(II)-l-histidine system
Coordination chemistry of copper(II)-l-histidine systemOrigin of the sagaStructures of the species in the copper(II)-l-histidine systemMHL speciesMH2L2 and ML speciesMHL2 speciesPhysiological ML2 speciesStructural studies in solutionModel compounds of the structural arrangement of ML2 complexX-ray crystal structure of ML2
MH-1L2 species
Copper(II)-l-histidine complex as a copper transporter in humansEquilibrium in the exchangeable pool of copper(II) in human bloodTissue and cellular uptake of copper facilitated by l-histidineKinetics of copper exchange with albumin
Applications of copper(II)-l-histidine complex as a therapeutic agentMenkes diseaseInfantile hypertrophic cardioencephalomyopathy
ConclusionAcknowledgementsReferences